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3 results on '"Department of Hematology, Necker-Enfants Malades University Hospital, AP-HP"'

1. Mutations in the SRP54 gene cause severe congenital neutropenia as well as Shwachman-Diamond–like syndrome

Author

Aline Schmidt, Felipe Suarez, Eric Oksenhendler, Barbara Schmaltz-Panneau, Philippe Bensaid, Jean Donadieu, Gérard Pierron, Yves Bertrand, Aurélie Docet, Blandine Beaupain, Vincent Barlogis, Frédéric Bauduer, Séverine Clauin, Christine Bellanné-Chantelot, Isabelle Plo, Isabelle Callebaut, Nathalie Aladjidi, Françoise Mazingue, Sylvie Souquere, Iléana Antony-Debré, Cécile Stoven, Thuan Chong Quah, Isabelle Pellier, Caroline Marty, Hubert Journel, Thierry Leblanc, Marie Ouachee, Gandhi-Laurent Damaj, Liana Carausu, Claire Fieschi, Odile Fenneteau, Véronique Saada, Claire Galambrun, Odile Boespflug-Tanguy, Marlène Pasquet, Brigitte Nelken, William Vainchenker, Claire Berger, Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Gustave Roussy (IGR), Service d'Hématologie Biologique [Hôpital Robert Debré, Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Muséum national d'Histoire naturelle (MNHN)-Institut de recherche pour le développement [IRD] : UR206-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Department of Hematology, Centre Hospitalier Universitaire (CHU), Faculté de Médecine, University of Normandie Caen, Department of Pediatric Hematology and Immunology, Robert Debré Hospital, AP-HP, Paris, Department of Pediatric Hematology, Immunology and Oncology, CHU, Angers, Department of Pediatrics, CHU La Réunion, Groupe Hospitalier Sud Réunion, Physiologie et physiopathologie des rétrovirus endogènes et infectieux (RETRO-ENDO), Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Unit of Pediatric Hematology, Centre d'Investigation Clinique 1401INSERM Centre d'Investigation Clinique Plurithématique, CHU Bordeaux, Pédiatrie et oncologie pédiatrique [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Côte Basque, Bayonne, Department of Pediatrics, Centre Hospitalier Argenteuil, Argenteuil, Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Department of Pediatric Hematology and Oncology, CHU, Saint-Etienne, Pediatric Hematology and Oncology Institute, Lyon, Department of Pediatric Hematology and Oncology, CHU Brest, Department of Clinical Immunology, Saint-Louis Hospital, AP-HP, Paris, Service d'Hématologie pédiatrique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Department of Hematology, CHU, Angers, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Department of Pediatric Hematology and Oncology, CHRU, Lille, Department of Pediatrics, National University Hospital, Singapore, Service d'hématologie-oncologie adultes, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris], Service d'Immuno-hématologie pédiatrique [Hôpital Robert Debré, Paris], Hôpital Robert Debré-Hôpital Robert Debré, Institut of Pediatric Hematology and Oncology, Lyon, Hématologie pédiatrique, CHU Toulouse [Toulouse], Laboratory of Hematology, Gustave Roussy, Villejuif, Department of Hematology, Necker-Enfants Malades University Hospital, AP-HP, Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University of Paris Descartes, CNRS UMR9196, Gustave Roussy, Villejuif, Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Département de biologie et pathologie médicales [Gustave Roussy], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Université Paris Descartes - Paris 5 (UPD5), Rétrovirus endogènes et éléments rétroïdes des eucaryotes supérieurs (UMR 9196), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier de la Côte Basque (CHCB), National University of Singapore (NUS), Sercice Hématologie, immunologie et oncologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Mécanismes cellulaires et moléculaires des désordres hématologiques et implications thérapeutiques = Molecular mechanisms of hematological disorders and therapeutic implications (ERL 8254), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)

Subjects
0301 basic medicine, Gene knockdown, Shwachman–Diamond syndrome, Mutation, business.industry, [SDV]Life Sciences [q-bio], Immunology, Cell Biology, Hematology, Neutropenia, medicine.disease, medicine.disease_cause, Biochemistry, 3. Good health, 03 medical and health sciences, 030104 developmental biology, Membrane protein, Unfolded protein response, medicine, Cancer research, Congenital Neutropenia, business, Exocrine pancreatic insufficiency, ComputingMilieux_MISCELLANEOUS
Abstract

Congenital neutropenias (CNs) are rare heterogeneous genetic disorders, with about 25% of patients without known genetic defects. Using whole-exome sequencing, we identified a heterozygous mutation in the SRP54 gene, encoding the signal recognition particle (SRP) 54 GTPase protein, in 3 sporadic cases and 1 autosomal dominant family. We subsequently sequenced the SRP54 gene in 66 probands from the French CN registry. In total, we identified 23 mutated cases (16 sporadic, 7 familial) with 7 distinct germ line SRP54 mutations including a recurrent in-frame deletion (Thr117del) in 14 cases. In nearly all patients, neutropenia was chronic and profound with promyelocytic maturation arrest, occurring within the first months of life, and required long-term granulocyte colony-stimulating factor therapy with a poor response. Neutropenia was sometimes associated with a severe neurodevelopmental delay (n = 5) and/or an exocrine pancreatic insufficiency requiring enzyme supplementation (n = 3). The SRP54 protein is a key component of the ribonucleoprotein complex that mediates the co-translational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER). We showed that SRP54 was specifically upregulated during the in vitro granulocytic differentiation, and that SRP54 mutations or knockdown led to a drastically reduced proliferation of granulocytic cells associated with an enhanced P53-dependent apoptosis. Bone marrow examination of SRP54-mutated patients revealed a major dysgranulopoiesis and features of cellular ER stress and autophagy that were confirmed using SRP54-mutated primary cells and SRP54 knockdown cells. In conclusion, we characterized a pathological pathway, which represents the second most common cause of CN with maturation arrest in the French CN registry.

Published
2018

2. Current Spectrum of Infections in Patients with X-Linked Agammaglobulinemia.

Author

Paccoud O, Mahlaoui N, Moshous D, Aguilar C, Neven B, Lanternier F, Suarez F, Picard C, Fischer A, Blanche S, Lecuit M, Hermine O, and Lortholary O

Subjects
Child, Preschool, Cross-Sectional Studies, Female, Humans, Immunoglobulin G immunology, Immunoglobulins, Intravenous immunology, Immunosuppressive Agents immunology, Infant, Male, Retrospective Studies, Agammaglobulinemia immunology, Genetic Diseases, X-Linked immunology, Infections immunology
Abstract

Outcome of patients with X-linked agammaglobulinemia (XLA) has improved with the widespread use of immunoglobulin replacement therapy (IgRT). There are few data on the spectrum of infections experienced by patients undergoing IgRT. We carried out a retrospective cross-sectional analysis of the records of XLA patients seen at Necker-Enfants Malades Hospital, Paris. For each infection, we evaluated infection site, microbial etiology, antibiotic prophylaxis, immunosuppressive treatment, IgRT route, and last known IgG trough level. Sixty patients were included, who cumulated a follow-up of 1470 patient-years. We recorded 188 infections, including 97 after initiation of IgRT. The rate of infection was highest before IgRT (0.66 vs. 0.06 per person-year (ppy), p < 0.001) and was higher after the age of 16 compared to before (0.14 vs. 0.05 ppy, p = 0.048). It was similar for patients receiving intravenous or subcutaneous Ig (0.09 vs 0.05 ppy, p = 0.54). The lungs and gastrointestinal tract accounted for 71% of infection sites. Forty-six (47%) infections occurred in patients receiving antibiotic prophylaxis. Sixteen (16.5%) infections occurred in patients receiving immunosuppressive therapy, which more frequently occurred after age 16 (35% vs. 2.4%, p < 0.001). The median IgG trough level prior to all infections was 8.4 g/L. Almost half (44.3%) of infections occurred with prior IgG trough levels > 8 g/L, and 16/97 (16.7%) in patients with trough levels > 10 g/L. Infection remains a significant issue in patients with XLA undergoing IgRT despite adequate IgG trough levels. Chronic inflammatory manifestations of X-linked agammaglobulinemia and immunosuppressive therapies may be significant drivers of infection during adulthood., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Published
2021
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3. Mutations in the SRP54 gene cause severe congenital neutropenia as well as Shwachman-Diamond-like syndrome.

Author

Bellanné-Chantelot C, Schmaltz-Panneau B, Marty C, Fenneteau O, Callebaut I, Clauin S, Docet A, Damaj GL, Leblanc T, Pellier I, Stoven C, Souquere S, Antony-Debré I, Beaupain B, Aladjidi N, Barlogis V, Bauduer F, Bensaid P, Boespflug-Tanguy O, Berger C, Bertrand Y, Carausu L, Fieschi C, Galambrun C, Schmidt A, Journel H, Mazingue F, Nelken B, Quah TC, Oksenhendler E, Ouachée M, Pasquet M, Saada V, Suarez F, Pierron G, Vainchenker W, Plo I, and Donadieu J

Subjects
Adolescent, Adult, Apoptosis, Autophagy, Bone Marrow Diseases metabolism, Bone Marrow Diseases pathology, Child, Child, Preschool, Congenital Bone Marrow Failure Syndromes, Exocrine Pancreatic Insufficiency metabolism, Exocrine Pancreatic Insufficiency pathology, Female, Humans, Infant, Infant, Newborn, Lipomatosis metabolism, Lipomatosis pathology, Male, Middle Aged, Neutropenia genetics, Neutropenia metabolism, Neutropenia pathology, Shwachman-Diamond Syndrome, Up-Regulation, Young Adult, Bone Marrow Diseases genetics, Endoplasmic Reticulum Stress, Exocrine Pancreatic Insufficiency genetics, Lipomatosis genetics, Mutation, Neutropenia congenital, Signal Recognition Particle genetics
Abstract

Congenital neutropenias (CNs) are rare heterogeneous genetic disorders, with about 25% of patients without known genetic defects. Using whole-exome sequencing, we identified a heterozygous mutation in the SRP54 gene, encoding the signal recognition particle (SRP) 54 GTPase protein, in 3 sporadic cases and 1 autosomal dominant family. We subsequently sequenced the SRP54 gene in 66 probands from the French CN registry. In total, we identified 23 mutated cases (16 sporadic, 7 familial) with 7 distinct germ line SRP54 mutations including a recurrent in-frame deletion (Thr117del) in 14 cases. In nearly all patients, neutropenia was chronic and profound with promyelocytic maturation arrest, occurring within the first months of life, and required long-term granulocyte colony-stimulating factor therapy with a poor response. Neutropenia was sometimes associated with a severe neurodevelopmental delay (n = 5) and/or an exocrine pancreatic insufficiency requiring enzyme supplementation (n = 3). The SRP54 protein is a key component of the ribonucleoprotein complex that mediates the co-translational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER). We showed that SRP54 was specifically upregulated during the in vitro granulocytic differentiation, and that SRP54 mutations or knockdown led to a drastically reduced proliferation of granulocytic cells associated with an enhanced P53-dependent apoptosis. Bone marrow examination of SRP54 -mutated patients revealed a major dysgranulopoiesis and features of cellular ER stress and autophagy that were confirmed using SRP54 -mutated primary cells and SRP54 knockdown cells. In conclusion, we characterized a pathological pathway, which represents the second most common cause of CN with maturation arrest in the French CN registry., (© 2018 by The American Society of Hematology.)

Published
2018
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